Corticolimbic dopamine neurotransmission is temporally dissociated from the cognitive and locomotor effects of phencyclidine

Abstract

The behavioral syndrome produced by phencyclidine (PCP) and its analog ketamine represents a pharmacological model for some aspects of schizophrenia. Despite the multifaceted properties of these drugs, the main mechanism for their psychotomimetic and cognitive-impairing effects has been thought heretofore to involve the corticolimbic dopamine system. The present study examined the temporal relationship between alterations in corticolimbic dopamine and glutamate neurotransmission and two dopamine-dependent behavioral effects of PCP in the rodent that have relevance to the clinical phenomenology, namely, impairment of working memory, which is used to model the frontal lobe deficits associated with schizophrenia, and hyperlocomotion, which is used as a predictor of the propensity of a drug to elicit or exacerbate psychosis. PCP increased dopamine and glutamate efflux in the prefrontal cortex and nucleus accumbens, as measured by microdialysis. The increase in dopamine in both regions remained elevated well above baseline 2.5 hr after the injection, at which time the experiment was terminated. However, locomotor activity returned to baseline in <2 hr after injection. Furthermore, impaired performance in a discrete trial delayed alternation task, a rodent working memory task, was only evident up to 60 min after PCP injection; animals tested 80 min after injection, when cortical dopamine release was elevated at 300% of baseline, did not exhibit impaired performance. These findings indicate that activation of dopamine neurotransmission is not sufficient to sustain PCP-induced locomotion and impairment of working memory. Thus, effects of PCP, including a glutamatergic hyperstimulation, may be necessary to account for the psychotomimetic and cognitive-impairing effects of this drug.

Fig. 1.

Effect of PCP (5 mg/kg, i.p.) on the extracellular levels of dopamine in the prefrontal cortex. The topillustrates the data in terms of percentage of baseline (mean ± SEM of the three basal values obtained immediately before the injection), and the bottom indicates the absolute dopamine concentration in the dialysis samples not corrected for probe recovery. Two-way ANOVA with time as the repeated measures indicated a significant group × time effect (p < 0.001) between the PCP (n = 7) and saline (n = 6) groups. Asterisks indicate significant differences from the saline-treated group corresponding to the same postinjection time.

Fig. 2.

Effect of PCP (5 mg/kg, i.p.) on the extracellular levels of glutamate in the prefrontal cortex. The topillustrates the data in terms of percentage of the mean ± SEM of the three basal values obtained immediately before the injection, and the bottom is the absolute dopamine concentration in the dialysis samples not corrected for probe recovery. Two-way ANOVA with time as the repeated measures indicated a significant group × time effect (p < 0.04) between the PCP (n = 7) and saline (n = 6) groups. Asterisks indicate significant differences from the saline-treated group corresponding to the same postinjection time.

Fig. 3.

Time-dependent effect of intraperitoneal injection of PCP on discrete trial delayed alternation performance. Only two rats were properly tested at 20 min after injection, both of which performed at 50% correct. (Three other rats tested at this time ran up and down the main alley of the maze and did not enter the side arms or remained in the start box exhibiting profound head rolling.) Animals tested 40 and 60 min after PCP injection showed significant impairment compared with the saline-treated group (p < 0.05). Rats tested 80 min after PCP injection did not display an impairment.

Fig. 4.

Temporal comparison of the increase in extracellular levels of dopamine and glutamate (displayed as percent of preinjection value) and performance in delayed alternation paradigm corresponding to the time that the neurochemical analysis was performed after PCP injection.

Fig. 5.

Effect of PCP (5 mg/kg, i.p.) on the extracellular levels of dopamine in the nucleus accumbens. The topillustrates the data in terms of percentage of the mean ± SEM of the three basal values obtained immediately before the injection, and the bottom is the absolute dopamine concentration in the dialysis samples not corrected for probe recovery. Two-way ANOVA with time as the repeated measures indicated a significant group × time effect (p < 0.01) between the PCP (n = 8) and saline (n = 8) groups. Asterisks indicate significant differences from the saline-treated group corresponding to the same postinjection time.

Fig. 6.

Effect of PCP (5 mg/kg, i.p.;n = 6) or saline (n = 6) on the extracellular levels of glutamate in the nucleus accumbens. Thetop illustrates the data in terms of percentage of the mean ± SEM of the three basal values obtained immediately before the injection, and the bottom is the absolute dopamine concentration in the dialysis samples not corrected for probe recovery. PCP produced a significant increase in glutamate levels relative to preinjection values (p < 0.05, using ANOVA with time as the repeated measures). Asterisks indicate significant differences from preinjection values.

Fig. 7.

Effect of PCP and saline injection on locomotor activity (top) and stereotypy score (bottom). Two-way ANOVA with time as the repeated measures indicated a significant group × time effect (p < 0.001) between the PCP (n = 8) and saline (n = 8) groups. Asterisks indicate significant differences from the saline-treated group corresponding to the same postinjection time.

Fig. 8.

Correlational analysis for concomitant 20 min measurements (top) and the temporal relationship (bottom) between the locomotor activity and extracellular levels of dopamine in the nucleus accumbens after PCP.

Fig. 9.

Correlational analysis for concomitant 20 min measurements (top) and the temporal relationship (bottom) between the locomotor activity and extracellular levels of glutamate in the nucleus accumbens after PCP.